Main

Linear E- and Z-trisubstituted alkenes occur widely in nature and are used regularly in preparative chemistry1,2, for example in catalytic enantioselective hydrogenations3, allylic substitutions4, or conjugate additions5. There are several approaches for the synthesis of acyclic trisubstituted alkenes, but these suffer from key shortcomings. Unless an α-alkoxy ketone is involved6, Wittig-type transformations are minimally stereoselective7,8. Protocols for converting alkynes or carbonyl-containing compounds to trisubstituted alkenes involve lengthy sequences9,10,11, strongly acidic or basic conditions10,11,12,13, and/or just one stereoisomer12,14 can be accessed (see Supplementary Information 1 for extended bibliography). The higher-energy Z isomers can be prepared only if a suitable directing group is present15,16. There are no catalytic, high-yielding, broadly applicable, and stereoselective methods for accessing trisubstituted alkenes, particularly one that can deliver either stereoisomer. Especially desirable would be strategies that provide access to E- or Z-trisubstituted alkenyl chlorides and bromides, which are found in biologically active natural products17 and may be used to synthesize numerous other alkenes through cross-coupling.

The main challenges

There are just a small number of reports on the synthesis of trisubstituted alkenes by cross-metathesis18,19,20,21. In two cases is stereoisomerism a concern18,20 and, in each instance, reactions are either minimally selective or afford the E isomer preferentially because stereoselectivity arises from substrate control.

Designing methods for kinetically controlled E- or Z-selective22,23 synthesis of trisubstituted alkenes is difficult24 for several reasons. The metallacyclobutane intermediates are relatively hindered, and there is a smaller energy difference between the E and Z isomers25 compared to that of 1,2-disubstituted alkenes. There is also an inherent lack of chemoselectivity: in cross-metathesis, when a trisubstituted alkene is desired, typically one starting material is a monosubstituted and the other is a 1,1-disubstituted alkene, both containing an unsubstituted terminal alkenyl methylene unit. Consequently, ethylene can be generated as the by-product of cross-metathesis or as a result of homo-metathesis of the less hindered (more reactive) substrate. Ethylene formation leads to an unstable methylidene complex26, resulting in low turnover numbers and/or frequencies. It was therefore not surprising that our initial efforts to extend our recent approach for the synthesis of disubstituted alkenyl halides by cross-metathesis catalysed by molybdenum-based complexes27,28 to their trisubstituted variants proved to be less than straightforward. The reaction of 1,1-disubstituted alkene 1a with Z-1,2-dichloroethene (Z-2; Fig. 1a) needed relatively high loading (10 mol%) of the molybdenum complexes Mo-1 (ref. 27) or Mo-2 (ref. 28) and a long reaction time (12 h) to furnish 3a in 81% and 65% yield with no more than moderate stereoselectivity (80:20 and 70:30 E:Z, respectively); control experiments indicated minimal post-metathesis isomerization. The transformation involving 4-tert-butyl-α-methyl styrene was less efficient (3b, 30% yield) but more stereoselective, owing to better substrate control.

Figure 1: The challenge of developing stereoselective trisubstituted alkene cross-metathesis.
figure 1

a, The reaction between 1,1-disubstituted alkene 1a and Z-2 required 10 mol% loading for ≥ 72% conversion in 12 h, affording E-3a in ≤ 80:20 E:Z ratio. Formation of E-3b was sluggish but more stereoselective owing to substrate control. b, Inefficiency and low stereoselectivity is probably due to the poor stability of methylidene v and the minimal size difference between the substituents in 1a. c, With a trisubstituted alkene (E-6), catalysis is initiated by reaction with Z-2 to generate iii, which is more robust than a methylidene complex. Moreover, the involvement of metallacyclobutane vii (rather than iv) as an intermediate should lead to superior stereoselectivity. Ar, aryl; Conv., conversion; Ph, phenyl; t-Bu, tert-butyl. Conversion and isomeric ratios are determined by the analysis of 1H NMR spectra of unpurified mixtures; yields are for isolated and purified products. See the Supplementary Information for details.

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The above transformations begin with monosubstituted alkene 4 being generated exclusively (Fig. 1b), revealing that initiation involves the reaction of molybdenum complex i with 1a (not Z-2) to give disubstituted alkylidene ii. Reaction of ii with Z-2 may subsequently lead to the putative chloro-substituted alkylidene iii (ref. 29), which can then react with 1a to give methylidene v and 3a via metallacyclobutane iv, with the quaternary carbon centre at the less hindered Cβ (ref. 27) (for more detailed analysis, see Extended Data Fig. 1). Hence, despite the absence of a monosubstituted alkene, sufficient methylidene iv is still generated such that the short lifetime of methylidene species v translates to the need for high catalyst loadings and extended reaction times. High E selectivity is possible only when one Cβ substituent in iv is much larger.

More highly substituted alkenes as substrates

Use of a trisubstituted alkene, such as E-6, could improve efficiency and stereoselectivity (Fig. 1c). Complex i would react first with Z-1,2-dichloroethene (Z-2 versus E-6) to furnish chloroalkylidene iii; indeed, treatment of a mixture of Z-2 and E-6 with Mo-1 or Mo-2 generated chloroalkene 5 exclusively (based on 1H NMR analysis). Reaction via metallacyclobutane vii would be more stereoselective compared to the less substituted iv, because the competing addition mode would yield a less stable metallacyclobutane with the Cα methyl group oriented towards the larger aryloxide ligand. Another advantage would be the involvement of ethylidene vi (as opposed to methylidene v) as an intermediate, leading to a longer catalyst lifetime and improved efficiency. If successful, a solution would emerge based on the counterintuitive principle that efficiency and stereoselectivity can be improved by using a more hindered substrate.

The possibility of a trisubstituted alkene substrate poses new challenges. One is the need to promote efficient reactions of more highly substituted alkenes, and if trisubstituted alkenes are difficult to obtain, it can be questioned why their use as starting materials merits consideration. The answer is that some trisubstituted alkenes can be easily synthesized from readily available starting materials by catalytic cross-coupling.

E- and Z-trisubstituted alkenyl chlorides

We prepared E-6 (ref. 30) (Fig. 2a) through hydroboration of styrene and cross-coupling of the resulting alkylborane with commercially available E-2-bromo-2-butene (E-7; 85% yield, >98% E). Subjecting E-6 and E-2 (used without purification) to 1.0 mol% Mo-2 afforded E-3a in 81% yield (>98% conversion) and 95:5 E:Z selectivity after just four hours (compared to 65% yield and 70:30 E:Z, 10 mol% Mo-2, 12 h); reaction with Z-2 was similarly stereoselective but the yield was lower (50%). Cross-coupling of arylboronic acid 8, which is commercially available, and E-7 delivered E-9 in 81% yield (>98% E); the ensuing cross-metathesis with 3.0 mol% Mo-1 and Z -2 afforded E-3b in 90% yield and >98% stereoretention after four hours (compared to 30% yield, 10 mol% Mo-1, 12 h; Fig. 1a.

Figure 2: Synthesis of Z- and E-trisubstituted alkenyl chlorides.
figure 2

a, E-trisubstituted alkene substrates can be accessed by hydroboration of a monosubstituted alkene followed by cross-coupling with E-7. Subsequent cross-metathesis with Z- or E-2 was highly efficient, affording products in exceptional isomeric purity. The synthesis of E-3b shows an alternative way of merging cross-coupling and cross-metathesis. The approach is broadly applicable. b, Z-trisubstituted alkenyl chlorides may be accessed efficiently. c, Differences in steric pressure in metallacyclobutanes leading to E- and Z-trisubstituted alkene products provides an explanation for why transformations leading to the latter isomers are less selective: the energy difference between I and II (leading to E isomers) is larger than that separating III and IV (to give Z isomers). 9-BBN, 9-borabicyclo[3.3.1]nonane; Bn, benzyl; Boc, tert-butoxycarbonyl; comm. avail., commercially available; DMF, dimethylformamide; dppf, 1,1′-bis(diphenylphosphino)ferrocene; Fc, ferrocenyl; pin, pinacolato; PMB, para-methoxybenzyl; RL, larger substituent; RS, smaller substituent; THF, tetrahydrofuran. Conversion and isomeric ratios are determined by the analysis of 1H NMR spectra of unpurified mixtures; yields are for isolated and purified products. See the Supplementary Information for details.

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E-Trisubstituted alkenyl chlorides 3c–h (Fig. 2a) were isolated in 56–91% yield and 93:7 to >98:2 E:Z selectivity. The trialkylaluminium reagents necessary for a zirconocene-catalysed carbometallation approach are not compatible with an epoxide31 (see 3c; lower yield due to difficult purification), a carboxylic ester (see 3e), a B(pin) (pin, pinacolato) group (see 3f) or a Boc-protected (Boc, tert-butoxycarbonyl) indole32 (see 3h). Reactions leading to dienes 3e and 3f were chemoselective, as cross-metathesis involving the electron-deficient but less substituted enoate or alkenyl–B(pin) groups is less favoured. Compounds 3b, 3g and 3h were secured in >85% yield and as a single stereoisomer, although more catalyst was required for 3h. Catalytic stereoretentive cross-metathesis with aryl alkenes is often difficult28.

Z-Trisubstituted alkenyl halides were synthesized by incorporating a minor procedural change (Fig. 2b). With commercially available Z-7, by an otherwise identical sequence to before, we prepared Z-6 in 75% yield as a single stereoisomer (>98% Z). Cross-metathesis with Z-2 and 3.0 mol% Mo-2 afforded Z-3a in 86% yield and 91:9 Z:E ratio after four hours. Additional examples are provided in Fig. 2b (3i–m). Halogenated allyl–B(pin) compound 3k, amenable to catalytic diastereo- and enantioselective additions to electrophiles, was isolated in 83% yield and 95:5 Z:E ratio. Preparation of 3l (89% yield, 86:14 Z:E) shows that a Lewis basic trialkylamine is tolerated. Reactions with aryl alkenes were efficient but less stereoselective than the related E-selective processes (for example, Z-3b, 65% yield (pure Z isomer), 79:21 Z:E). Z-Trisubstituted alkenes cannot be accessed by carboalumination without an appropriate directing group13,15.

Figure 3: Synthesis of Z- and E-trisubstituted alkenyl bromides.
figure 3

a, Attributes of a molybdenum alkylidene dictate that reaction with Z-10 preferentially generates a bromo-substituted alkylidene and an alkenyl fluoride by-product (for example, 11) via A. The subsequent steps should afford E- or Z-trisubstituted alkenyl bromides (Cycles 2 and 3, respectively). b, Reaction between Z-10 and E-6 delivered E-12a in 90% yield, 95:5 bromo:fluoro ratio, and > 98:2 E:Z selectivity; with Z-6, Z-12a was obtained in 66% yield, 83:17 bromo:fluoro ratio, and 5:95 E:Z selectivity. The difference in bromo:fluoro selectivity probably originates from the increased steric pressure in metallacyclobutane ix (Cycle 3, Fig. 3a), leading to x as an intermediate and an alkenyl fluoride by-product (via ii, Fig. 1). When 1a was used, 12a was generated with lower efficiency and stereoselectivity. c, The method has considerable scope and may be used with substrates containing acetals. PMP, para-methoxyphenyl. Conversion and isomeric ratios are determined by the analysis of 1H NMR spectra of unpurified mixtures; yields are for isolated and purified products. See the Supplementary Information for details.

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Transformations affording E-alkenyl chlorides (Fig. 2a) are generally more stereoretentive compared to those furnishing Z isomers (Fig. 2b). This can be rationalized by considering repulsive interactions within the metallacycle intermediates. For processes affording E alkenes (Fig. 2c, left), I is probably favoured as an intermediate because of the steric pressure in II, caused by the nearness of the methyl group oriented towards the sizeable aryloxide ligand (Cα substituents are nearer to the sizeable ligand compared to those at Cβ, ref. 27). Similarly notable is the proximity of the larger alkenyl group (RL) and the adjacent chloride substituent (versus RS, the smaller alkene substituent, and Cl in I). With processes affording Z isomers (Fig. 2c, right), the energy gap between III and IV is probably smaller, because now it is within the metallacycle leading to the Z alkene (III) that RL and the chlorine atom are oriented in the same direction. Therefore, Z:E ratios are lower for reactions with a larger group at the fully substituted carbon of the alkene (for example, the aryl group in 3b), as there is more steric pressure in III with a phenyl group as the larger Cβ substituent (RL). Analogously, Z-3k was generated with greater stereoretention (95% compared to ≤91% Z) because the substrate, accessed by a phosphine–Ni-catalysed diene hydroboration33, bears a larger n-Bu unit cis to the CH2B(pin) moiety (versus Me); IV is destabilized further by a stronger repulsion between the Cα substituent and the aryloxide ligand (n-Bu instead of Me).

E- and Z-trisubstituted alkenyl bromides

The pathway in Fig. 1c and the formerly established electronic and steric factors27,28 suggest that, with a dihaloalkene containing two different halogen atoms (for example, Z-1-bromo-2-fluoroethene (Z-10), Fig. 3a), the metallacyclobutane (see A, Cycle 1, Fig. 3a) generating alkylidene iii′ and an alkenyl fluoride should be favoured. Indeed, treatment of Mo-1 or Mo-2 with Z-10 afforded fluoro-substituted alkene 11 (based on 1H NMR analysis). The ensuing transformation via alkylidene iii′ and metallacyclobutane vii′ (Cycle 1, Fig. 3a) would then give the alkenyl bromide product. This is unlike the reactions with mono- or 1,2-disubstituted alkenes, which involve bromo-substituted alkylidenes and produce alkenyl fluorides28.

In practice (Fig. 3b, left), with 1.0 mol% Mo-2, cross-metathesis between Z-10 and E-6 afforded trisubstituted alkenyl bromide E-12a in 95:5 bromo:fluoro selectivity, 90% yield (pure bromide) and with complete retention of stereochemistry (>98% E). The transformation involving Z-10 and Z-6 generated Z-12a in 66% yield (pure bromide) and 95% stereoisomeric purity. Akin to reactions of alkenyl chlorides (Fig. 2), when 1,1-disubstituted alkene 1a was used (instead of Z- or E-6; Fig. 3b), 12a was formed with much lower stereoselectivity (70:30 E:Z). Additional cases are shown in Fig. 3c (12b–f), including 12f, which contains acetal groups; these are problematic with trialkylaluminium compounds34.

The preference for the bromo-alkenyl product is higher for the E isomers (92:8–97:3 compared to 83:17–89:11 bromo:fluoro, respectively). This might be because, for Z-alkene substrates, steric repulsion between the alkyl group and bromine in the more favourable ix renders formation of the alternative metallacycle x more competitive (Cycle 3, Fig. 3a). The collapse of x would generate disubstituted alkylidene ii (Fig. 1b), which can react with Z-10 with the expected sense of selectivity (see A, Cycle 1, Fig. 3a) to give more of the alkenyl fluoride by-product. Reactions with 1,2-dibromoethene were considerably less efficient.

Other types of E- or Z-trisubstituted alkenes

Trisubstituted alkenes with a longer-chain alkyl unit (that is, longer than a methyl group) can be prepared (Fig. 4a). Hydroboration35 of 4-octyne followed by cross-coupling36 afforded 13 in 82% overall yield (>98% E). Subsequent cross-metathesis generated chloride 14 in 92% yield and 82:18 E:Z selectivity; bromide 15 was obtained in 92:8 bromo:fluoro selectivity, 80% yield (pure bromide) and the same stereoisomeric purity. The diminished stereoretention probably originates from the smaller size difference between the alkyl groups (that is, n-Pr and (CH2)4Ph) positioned at Cβ of the corresponding metallacyclobutanes. This strategy is especially attractive when the use of higher order, less readily available trialkylaluminium reagents would be a less desirable option (compared to Me3Al)15.

Figure 4: Synthesis of E- or Z-trisubstituted non-halogenated alkenes.
figure 4

a, Trisubstituted alkenes with substituents other than a methyl group can be prepared efficiently and stereoselectively. b, The present strategies may be used to synthesize non-halogenated alkenes. An isomeric mixture of 1,2-disubstituted alkenes may be used, and sterically less hindered Mo-3 (versus Mo-2) allowed for higher efficiency to be attained. c, Z-trisubstituted alkenes may be obtained in a similar manner (for example, Z-6); as with the alkenyl halides, reactions are less stereoretentive than when E isomers are generated. For higher yield in these instances, involving especially hindered metallacyclobutanes, a molybdenum chloride complex is required. Mes, 2,4,6-trimethylphenyl; PMB, para-methoxybenzyl; TBS, tert-butyldimethylsilyl. Conversion and isomeric ratios are determined by the analysis of 1H NMR spectra of unpurified mixtures; yields are for isolated and purified products. See the Supplementary Information for details.

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Non-halogenated trisubstituted alkenes may be prepared efficiently and stereoselectively (Fig. 4b, c). Treatment of E-6 with a 61:39 E:Z mixture of 1,2-disubstituted homoallylic ether 16 and 5.0 mol% Mo-3 (ref. 37) led to the formation of E-17 in 52% yield and 93:7 E:Z ratio (Fig. 4b). Similarly, E-18 was obtained in 69% yield as a single stereoisomer (>98% E). Because of the more sizeable reaction partners (versus a Z-1,2-dihaloethene), the use of a less sterically congested complex with a mesityl-substituted (mesityl, 2,4,6-trimethylphenyl) aryloxide ligand led to higher efficiency (that is, Mo-3 instead of Mo-2). An advantage here is that, because the catalyst can react with either 1,2-disubstituted alkene isomer to generate the same alkylidene, this starting material need not be stereoisomerically pure; cross-metathesis between a 1,1-disubstituted and an E- or Z-1,2-disubstituted alkene leads to stereoisomeric mixtures (see Fig. 1b, c).

Z-Trisubstituted alkenes (Z-18 and Z-20, Fig. 4c) were accessed in a similar manner. Because these transformations proceed via more congested metallacycles (see III–IV versus I–II, Fig. 2c), the use of monoaryloxide chloride species Mo-4 (ref. 38) led to improved efficiency; for example, Z-18 was isolated in 28% yield when pyrrolide complex Mo-3 was employed (compared to 64% yield). Molybdenum chloride complexes are ineffective in promoting transformations that afford alkenyl halides, because decomposition of the purported chloro- or bromo-substituted metallacyclobutanes is probably facile38. The present approach complements a recent study regarding the stereoselective synthesis of trisubstituted alkenes starting from carboxylic acids and involving alkenylzinc reagents, which are often derived from alkenyl halide precursors39.

Synthesis of biologically active compounds

The first application that illustrates utility pertains to the stereoselective synthesis of naturally occurring antifungal agent indiacen B32,40,41 (Fig. 5a). Diene E-3f was prepared from enal 21 and bis((pinacolato)boryl)methane (both commercially available) via 22 in two steps42, including a chemoselective and stereoretentive cross-metathesis, in 91% yield and 96% E:Z ratio. Indiacen B was obtained after an additional catalytic step in 65% yield. The three-step route, affording the target molecule in 54% overall yield, is in contrast to a previously reported seven-step synthesis32, which involved zirconocene-catalysed methyl-aluminium addition to an alkyne, generating the final product in 16% overall yield.

Figure 5: Synthesis of biologically active compounds.
figure 5

a, Indiacen B (antifungal) was synthesized stereoselectively in 54% overall yield in three steps. b, For synthesis of coibacin D (anti-inflammatory), diene 25, prepared by catalytic cross-coupling, was transformed to the desired target by a sequence of four catalytic processes: two chemo- and stereoselective cross-metathesis reactions to give E-3n via 26, a cross-coupling reaction to afford 28 and a Ru-dithiolate catalysed cross-metathesis. Dienoate 29 may be used to prepare kimbeamide A (antitumour). c, Cross-metathesis of homoallylic silyl ether 30, synthesized in 83% yield from E-7, afforded E-12g in 88:12 bromo:fluoro ratio. Subsequent cross-coupling afforded 31, a fragment used in a total synthesis of pateamine A (immunosuppressant). DABCO, 1,4-diazabicyclo[2.2.2]octane; DME, dimethoxyethane; dpephos, bis[(2-diphenylphosphino)phenyl]ether; LiTMP, lithium 2,2,6,6-tetramethylpiperidide; TBSOTf, tert-butyldimethylsilyl triflate; TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy. Conversion and isomeric ratios are determined by the analysis of 1H NMR spectra of unpurified mixtures; yields are for isolated and purified products. See the Supplementary Information for details.

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The preparation of antileishmanial and anti-inflammatory compound coibacin D43 highlights a series of five catalytic processes (Fig. 5b). Stereoisomerically pure E,E-diene 25 was accessed in 72% yield by a two-step procedure involving hydroboration of 2-butyne and cross-coupling of the resulting alkenylboronic acid with allylic alcohol 24 (ref. 44). Compound E-3n was then obtained via E-alkenyl–B(pin) intermediate 26 through two chemoselective and stereoretentive cross-metathesis reactions. The first was the conversion of 25 to 26 by a transformation involving 3.0 mol% Mo-3 and vinyl–B(pin); use of the slightly bulkier complex Mo-3 (instead of Mo-1) allowed for exceptional stereocontrol (see Extended Data Fig. 2 for details), and the less hindered aryl alkene reacted exclusively. A second cross-metathesis was performed with 3.0 mol% Mo-2 and 1,2-dichloroethene Z-2 (5.0 equivalents), delivering E-3n in 59% yield and 97:3 E:Z selectivity; in this case, despite being more sterically encumbered, it was the trisubstituted alkene that reacted preferentially. Homoallylic alcohol 28 was accessed in 76% yield after another efficient and chemoselective cross-coupling between E-3n and 27. This was followed by a third, kinetically controlled chemoselective cross-metathesis with 28, Z-2-butene-1-4,diol and catechothiolate complex Ru-1 (refs 45, 46). The resulting Z-allylic alcohol, generated in 94:6 Z:E selectivity, was transformed to racemic coibacin D in 57% overall yield (>98:2 E,E at the acyclic alkene sites). Coibacin D was accordingly obtained in seven steps (longest linear sequence), 12% overall yield, and as a single alkene isomer, comparing favourably with the previously reported 4% overall yield after six steps to give racemic coibacin D as a 75:25 mixture of alkene isomers47. Moreover, alkenyl chloride E-3n was converted to dienoate 29 (70% yield, >98% E), a compound applicable to the synthesis of antitumour agent kimbeamide A48. The requisite amine fragment has been prepared through kinetically E-selective cross-metathesis27.

Alkenyl chlorides can be ineffective in cross-coupling and, in such cases, the corresponding bromoalkenes are required. One instance relates to the stereoselective synthesis of enyne 31 (Fig. 5c), a compound used to prepare pateamine A49, a natural product with immunosuppressant and anticancer properties50. Conversion of E-7 to homoallylic silyl ether 30 involved enantiomerically pure and commercially available S-propylene oxide, and was accomplished in two straightforward steps. Cross-metathesis between 30 and Z-1-bromo-2-fluoroethene (Z-10; 3.0 equivalents) with 5.0 mol% Mo-5 afforded E-12g in 88:12 bromo:fluoro selectivity and as a single alkenyl bromide isomer. A catalyst with a smaller aryloxide ligand was used to achieve high efficiency because a metallacyclobutane with a larger Cβ substituent must be accommodated (for example, 63% conversion to E-12g with Mo-2 under otherwise identical conditions). Cross-metathesis was again followed by cross-coupling, this time between E-12g and 3,3-diethoxy-1-propyne (commercially available). Cross-coupling with the related alkenyl chloride was ineffective (less than 2% conversion). Unmasking of the diethyl acetal group afforded 31 (41% overall yield for three steps). The fragment was therefore synthesized by a shorter route (five compared to eight steps) and in similar yield (34%, compared to the 33% overall yield reported previously49).

Conclusions

We demonstrate that there are two crucial factors for the successful development of kinetically controlled stereoretentive cross-metathesis reactions that afford trisubstituted alkenes. Various trisubstituted alkene substrates must be readily accessible in high stereoisomeric purity, and a set of catalysts that can catalyse reactions between tri‐ and 1,2‐disubstituted alkenes efficiently and stereoselectively must be available. Accordingly, we show that a sequence beginning with cross-coupling between E- or Z-trisubstituted 2-bromo-2-butene and an organoboron compound and then a stereoretentive cross-metathesis with an appropriate molybdenum-based complex furnishes E- or Z-trisubstituted alkenes efficiently and in high stereoisomeric purity. The approach, which merges cross-coupling with cross-metathesis, underlines a key difference between two major classes of catalytic processes. Substrates in cross-coupling are more distinct and chemoselectivity is less problematic, offering facile access to the necessary trisubstituted alkene substrates. Cross-metathesis can then be used to access a wider range of alkenes and in high stereoisomeric purity. The relationship between cross-coupling and cross-metathesis has another dimension: the E- or Z-trisubstituted alkenyl halides may be converted to other trisubstituted alkenes with little or no loss of stereochemical purity through one more cross-coupling.

By adopting the appropriate combination of two important catalytic C–C bond-forming transformations, we have been able to address a critical unresolved problem in chemical synthesis. The present study provides additional evidence regarding the unique attributes of stereogenic-at-molybdenum complexes as effective alkene metathesis catalysts, which further benefit from the possibility of their use as commercially available paraffin tablets51.

Data Availability

The authors declare that findings of this study are available within the paper and its Supplementary Information.